2-substituted-1, 3-propane dithiol-dicarbamates and 2-substituted-3-carbamoxy-propylthiol carbamates



United States Patent 3,264 333 Z-SUBSTITUTED 1,3 PRoPANE DITHIOL-DICAR-BAMATES AND, 2 -SUBSTITUTED-3-CARBAM- OXY-PROPYLTHIOL CARBAMATESPatented August 2, 1966 Bernard J. Ludwig, North Brunswick, N.J., JuliusDia- 5 o mond, Plymouth Meeting. Pa., and Wilfred A. Skinner, ll Jr.,Portola Valley, Califi, assignors to Carter Products, RR1C(OH1Sc CHm2ArSO OM Inc., New York, N.Y., a corporation of Maryland No Drawing.Filed Apr. 22 1963, Ser. No. 276,197 3 7 Claims. (Cl. 260-455) 0 Thisinvention relates to a new class of compounds 10 nglgwmsggrrm 2H2Ortnlowmsmg 2CH C OH which are 2-subst1tuted-1,3-propanedithioldicarbamates (1v) and 2-substituted-3-carbamoxypr0pylthiol carbamatesand (4) to methods for perparing them. The compounds of the 0 presentinvention have the following general structure: HO ON RR1C(CH2SH)2RR10(CH2SCNHz)z The monothiol carbamate compounds of this invention RCHzYGNHa are obtained by a similar series of reactions, except that instep 1 only one mole of aromatic sulfonyl halide is ZONE employed foreach mole of Z-substituted-1,3-propanediol.

2 H 2 The sequence of reaction is as follows:

ERIC/(CIIQOEDZ ArSO X where R and R represent hydrogen and hydrocarbonRR1(C 2 1OSO1Ar) BK radicals with at least one of said groups being ahydro- (2a) carbon radical, and Y and Z represent oxygen and sulfur withat least one of said groups being sulfur. The pre- 1| ferred compoundsof this invention are those where R q 2 2 S z aC SM and R are loweralkyl or aryl. Specific examples of 0 the preferred dicarbamates of thisinvention are disclosed RR O(CH2OH)(O 2S 3C a) rSOzOM in Table I WhlChfollows:

TABLE I R CfizYi lNHz R1/ CH2Zfi3NH2 Calcd.- Found Compd. No. R R1 Y ZFormula 0 n N s o H N s n-C H s s 99-100 CgHmNnOgSg 43.2 7.3 11.2 25.643.1 7.2 11.0 25.3 sec-C H s s 94-96 CnHgqNzOgSg. 45.4 7.6 10.6 24.345.1 7.5 10.6 2348 c4215 s s 132-134 C7H N O1S1. 37.3 6.3 12.6 29.3 37.86.1 12.8 28.6 Phenyl-. s s 112-114 CgILgNQOgSg. 52.3 6.1 9.4 21.5 52.26.2 9.3 21.2 n-C H s 0 74-75 ctfimmoash 46.1 7.7 11.9 13.7 46.0 7.4 11.612.8 sec-0 E s 0 121-124 C10H7qNzO3s 48.4 8.1 11.3 12.9 48.1 7.9 11.012.8

The dithiol dicarbamate compounds of this invention are 34 obtained by(1) reacting an appropriate 2-substituted- 1,3-propanediol (I) with anaromatic sulfonyl halide, H OH H ll 1 O H H O e.g., p-toluene sultonylchlonde, to give an aromatic ERIC) 2 )(G 23 C 3) 2 sulfonate ester (11),(2) reacting said aromatic sulfonate 0 ester with an alkali metalthiolacetate in a dimethylform- 6O RRIWCHEOHXCHZSH) OHSPJOH amldesolvent to g1ve a thiol-acetate ester (III), (3) hydrolyzing saidthiolacetate ester to its corresponding dithiol (IV), and (4) convertingsaid dithiol to a dithiol- HO ON dicarbamate (V) by reacting it withcyanic acid (HOCN). RR'CmmOH) CHzSH) a Cyanic acid may be formed by thetreatment of an alkali H H cyanate with anhydrous hydrogen chloride. Theabove RR1O(0H1OCNH2)(GH4SONH,) reactions are as follows, Where R and Rare hydrogen or hydrocarbon radicals, Ar is an aromatic radical and Fromthe above desqlbefi reactlon step i 15 X is a halogen atom seen that thenovel thiol dicarbamates of this invention are prepared by reaction ofcyanic acid with the appropri- (1) ate thiol. The intermediate mono anddithiols from RmowmoH), 2ArSO X RRiow z a h ZHX which the thioldicarbamates of Table I are prepared are novel compounds.

The method for preparing the above-mentioned intermediate mono anddithiols is a novel method; this method being the steps 2 and 3, or 2aand 3a, described herein. before. Referring to step 2, or 2a, it shouldbeunderstood that the thiolacetate ester that is formed is not isolatedbut hydrolyzed to its corresponding. thiol in accordance with step 3, or3a.

More particularly, the above-mentioned method for: producing thiolcompounds may be described as follows:

A thiol compound having the structure R CHzYH R1 OHzZH where R and Rrepresent hydrogen and hydrocarbon radicals with at least one of saidgroups being a hydrocarbon radical, and Y and Z represent oxygen andsulfur with,

at least one of said groups being sulfur, is prepared by reacting-anaromatic sulfonate ester having the formula where D is selected from thegroup consisting of OH' and S OH3 radicals, and hydrolyzing saidthiolacetate ester to its corresponding thiol.

With respect to the above-described process for the: production ofthiols, it has been found that the use of dimethylformamide as a solventpermits the preparation: of many thiol compounds that is not possible ifordinary; organic solvents such as ether, ethanol and acetone are.employed.

In order to illustrate the invention more specifically, the followingexamples are given. Examples A and BI represent the preparation of2-substituted-Lil-propanedithiols and2-substituted-3-hydroxypropylthiols. Examples 1 and 2 illustrate thepreparation of 2-substituted- 1,3-propane dithiol dicarbamates and2-substituted-3-carbamoxypropylthiol carbamates.

Example A The following is a description of the preparation of2-methyl-2-propyl-1,3-propanedithiol:

p-Toluenesulfonyl chloride (191 g., 1 mole) was added portion-wise withstirring to a solution of 66 g. (0.5 mole) of2-methyl-2-pro-pyl-1,3-propanediol in 600 m1. of pyridine. Thetemperature was maintained at 18-20". After; standing overnight, themixture was poured into a solu-, tion of 1850 ml. methanol, 980 ml. ofwater and 730 ml. concentrated hydrochloric acid. The mixture wasrefrigerated overnight and the White crystalline product which separatedwas filtered off. The product. was 2-methyl-2-propyl-l,3-propanediolditosylate. Yield 160 g. A sample recrystallized from ethanol meltedat67- 69'.

1 Analysis.Calcd. for Cal-1 065 25, 14.56. Found: S, 14.85.

A'mixture of 48 g. i (0.111 'mole) of 2-methyl-2-pro-.

pyl-1, 3-propanediol ditosylate and 38 g. (0.333 mole) of dry potassiumthiolacetate in 300 ml.- of dimethylform-.

amide was heated atits reflux temperature for 18 hours. The cooled.mixture was poured into 500 ,ml. of water,

extracted with ether, the ether. extract Washed with water i and driedover :anhydrous sodiumsulfate; The filtered,

extract was distilled giving 11 g. (40%) of 2-methyl-2-Analysis.'-Calcd. for C H S r'C, 51.1; H, 9.8; S, 39.0.

Found: C, 51.3;iH, 9.7; S,-39.2.

Also prepared in the above-mentioned manner from,

the appropriate substituted 1,3-propanedithiol were the following:

this disclosure, unless otherwise indicated, reference to temperaturedegrees means centigradet.

Example 1 The following is adescription of the preparation of2-methyl-2-propyl-1,3-propanedithiol dicarbamate.

Into a stirred mixtureof 4.92 g. (0.03 mole). ofZ-methyl-2-propyl-1,3.-propanedithiol .46 g. (0.066 mole) of;

dried sodium-cyanate, and 25"g..of Drierite in 150 ml. of anhydrousalcohol-free. -chloroform' was passed a stream of hydrogen chloride: gasfor 7 hours. perature was maintained at 0 during thisadditi'on. Afterstanding overnightzat room temperature, the mixture was concentrated at50 under reduced pressure; The residue was extractedwith 100 ml. oftrichloroethylene, filtered, and-the filtrate, triturated with petroleumether to precipitate the product, 2-methyl-2-propyl-l,3-propanedi- The.:filtered.solid,. M.P.' -98 thiol 'dicarbamate. weighed 3.4 g- (38%).The material after recrystallization from benzene melted at 99100..

In the manner illustratedby the above example, other2-substituted-1,3-propanedithiol dicarbamates were pre pared fromthecorresponding propanediols. The physical constants and'analytical valuesfor these compounds are summarized in Table I.

Example B The followingis a description of the preparation of2-methyl-2-propyl-3 -hydroxypropylthiol.

7 To a solution of -13.2 g.'(0.1 mole) of 2-methyl-2-' propyl-l,3-propanediol, 7.9. g. (0.1 mole) pyridine and 25 ml. of anhydrousether. cooled to 50 C. was-added 19.0 g. (0.1 mole) ofp-toluenesu'lfonyl. 'chloride'.- The clear solution was maintained ata0-C. for 16' hours. The white precipitate of'zpyridin'e hydrochloride'wasfiltered and the ether solution washed with 5%, aqueous hydro-.

chloric acid and with waterand-dried over anhydrous sodium sulfate- Thesolution was concentratedin vacu-o, dissolved in the minimum amount 0flight petroleum ether and chromatographed on an alumina column; Elutionof the column with ether yielded 2-n1ethyl-2-propyl- S-hydroxypropyltosylate 'in-58% yield (16.6 g.) as a colorless oil; N 1.5107.

Armlysis.Calcd. for C H O S: C, 58.7; 'H, 7.75;'S,

tosylate and 111.4 g. .ofanhydrous potassium thiolacetate (prepared bytitration of distilled thiolacetic acid with 3 N' potassiumhydroxide inmethanol). :in '60 ml.- of di-..

methylformamide was heated at 95-100" C. under, nitrogen with stirringfor 2 hours. After standing overnight The temat room temperature undernitrogen, ether was added to the mixture, and the salts filtered. Theether was removed in vacuo, yielding 7.8 g. (81%) of the crudethiolester. The thiolester was hydrolyzed with 3.8 g. of sodiumhydroxide, ml. of water, and ml. of ethanol by stirring for 3 hours in astoppered flask. The clear, yellow solution was chilled, acidified with6 N hydrochloric acid and ether extracted. The extracts were washed withwater, dried over anhydrous magnesium sulfate, and 4.7 g. of product,2-methyl-2-propyl-3-hydroxypropylthiol, were obtained by distillationunder reduced pressure, B.P. 76-80 C./0.50.6 mm., n 1.4875.

Analysis.Calcd. for CqHwOSZ C, 56.7; H, 10.9; S, 21.6. Found: C, 56.9;H, 10.9; S, 21.4.

Also prepared in this manner from the appropriateZ-substituted-1,3-propanediol was 2-methyl-2-sec.-butyl-3-hydroxypropylthiol, B.P. -66/0.06 mm.

Example 2 The following is a description of the preparation of2-methyl-2-propyl-3-carbamoxypropylthiolcarbamate.

To a mixture of 2.6 g. (0.0175 mole) of the monothiol, 15 g. ofDrierite, ml. of anhydrous, alcoholfree chloroform, and 3.2 g. (0.049mole) of sodium cyanate cooled to 5 C. was added anhydrous hydrogenchloride for 5 hours with stirring. The slurry was filtered andconcentrated under vacuum. The clear oily residue was dissolved intrichloroethylene, and a crude product melting at 60-66 C. wasprecipitated, using petroleum ether, B.P. 30-60 C. Afterrecrystallization twice from chloroform-petroleum ether, purified2-methyl-2-propyl- 3-carbamoxypropylthiol carbamate was obtained in theform of white crystals, M.P. 7475.

In the manner illustrated by the above example, there was prepared2-methyl-2-sec-butyl-3-carbamoxypropylthiol carbamate. The physicalconstants and analytic values for these compounds are summarized inTable I.

The novel thiol carbamates of this invention possess anticonvulsant andmuscle relaxant properties.

The invention in its broader aspects is not limited to 4 the specificsteps, methods and compositions described but departures may be madetherefrom within the scope of the accompanying claims Without departingfrom the principles of the invention and without sacrificing its chiefadvantages.

What is claimed is: 1. Compounds having the following general structureR CHaYi lNHz R1 CHzZ (ENE:

References Cited by the Examiner UNITED STATES PATENTS 2,177,547 10/1939Jones 260455 2,436,137 2/1948 Biswell 260609' 2,829,171 4/1958 Doumani260609 2,863,899 12/1958 Harris 260455 2,901,501 8/1959 Wasson et a1.260455 3,073,848 l/1963 Wasson et al. 260482 X CHARLES B. PARKER,Primary Examiner.

0 D. D. HORWITZ, Examiner.

DALE R. MAHANAND, Assistant Examiner.

1. COMPOUNDS HAVING THE FOLLOWING GENERAL STRUCTURE